Amyloid-p (AP) peptide accumulation and aggregation are initiating events in the pathogenesis of Alzheimer's disease (AD). AB aggregation is concentration-dependent and can result from its overproduction, inefficient clearance, or both. LRP1 is a multifunctional lipoprotein receptor that modulates both AB production and clearance. While the fast endocytosis of LRP1 modulates the endocytosis and processing of amyloid precursor protein (APP) to influence AB production, the endocytic functions of both LRP1 and cell surface heparan sulfate proteoglycan (HSPG) facilitate cellular uptake and clearance of Ap. A major goal of this project is to examine the in vivo roles of LRP1 and HSPG in brain AP production and clearance in mice with altered gene expression by viral mediated or genetic approaches. Our recent collaborative work with the groups of David Holtzman and John Cirrito has also showed that synaptic activity regulates APP processing to AB, and that this regulation requires the endocytosis of APP. In addition to presynaptic mechanisms, AP producfion can also be regulated by a postsynaptic mechanism that involves NMDARs, which interact with LRP1. Therefore, we plan to determine whether LRP1/HSPGmediated Ap production or clearance is regulated by synaptic activity. Our overall hypothesis is that LRP1 and HSPG play critical roles in synaptic-dependent regulation of both AB production and clearance, and that dysregulation of these pathways leads to AP accumulation and aggregation in AD brains. To test our hypothesis, we will collaborate with Drs. David Holtzman and John Cirrito, who have extensive experience in modulating synaptic activity and measuring AB metabolism in vivo, to pursue three specific aims. In Aim 1, we will dissect the role of LRP1 in synaptic-dependent AB generation in vivo. In Aim 2, we will dissect the role of LRP1 and HSPG in synaptic-dependent AB clearance in vivo. In Aim 3, we will examine the specific roles of LRPI and HSPG in neurons and astrocytes in AB metabolism and amyloid pathology in vivo using conditional knockout mice. Together, these studies should allow us to dissect the molecular mechanisms underlying synaptic regulation of brain AP metabolism and may define novel targets for AD therapy.